1. Field of the Invention
The invention relates to an immunostimulating composition in the form of a thermoreversible oil-in-water (O/W) emulsion comprising a TLR4 agonist, called TLA4.
TLR4 (toll-like receptor type 4) is a receptor expressed by antigen-presenting cells of the immune system; it is involved in early defense mechanisms against gram-bacterial infections. The lipopolysaccharide (LPS) of gram-bacteria is the natural ligand for TLR4; it activates the receptor, which triggers a cascade of biochemical events, in particular the activation of Nf-Kappa B transcription factor, and the production of pro-inflammatory cytokines. Monophosphoryl lipid A, which comes from the hydrolysis of LPS, is also a ligand for TLR4, with the advantage that it is less toxic than LPS.
2. Summary of the Related Art
WO 2004/060396 describes formulations in the form of O/W emulsions containing a phospholipid adjuvant. The emulsions, which have a submicronic size, are obtained by means of a high pressure homogenizer (microfluidizer). The method of production uses high mechanical energies in order to obtain sufficiently great shear forces to reduce the size of the oil drops. According to this teaching, the emulsion obtained contains drops whose size is approximately 500 nm.
It is desirable to be able to have an alternative formulation to that proposed in that patent application, and especially one which can be obtained by a simpler method (not requiring specific shear technology), involving low energy while at the same time being reproducible, reliable and usable on a large scale; furthermore, the adjuvant formulation must be able to improve the effectiveness of vaccines, by increasing the immune response to an antigen, while at the same time not exhibiting any sign of toxicity which would be detrimental to the completely safe administration thereof.